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Out of Trend
I am in the process of writing SOP on Out of Trend. We are a contract research organization and are into providing analytical services (stability studies) apart from contract research and manufacturing
Would like to clarify whether OOT apply to batch release as well or does it apply to Out of Trend Stability results. Are there any guidelines for the same as it is available for OOS.
Edited Tue, Dec 24, 2013 3:31 PM
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OOT has not come into the official implementation because companies have been able to convince the regulatory authorities that OOT results may be due to instrumental or analytical errors. However, many regulatory bodies prefer to see variation in result trends. Mainly OOT is watched out for stability studies rather than batch release. Still I haven't heard that someone is insisting OOT analysis for batch release.
Thanks Jitendra. This is really helpful. Based on whatever i have read so far it appears that the main area where OOT needs to be addressed is the stability data. In some of articles the OOT stability alerts has been further classified into alerts like analytical, process control and compliance alerts in order of implied severity. The depth of investigation should increase as the alert level increases towards compliance alert.
What kind of statistical tools are used to handle OOT.
Identifying OOT stability results is a growing concern for FDA and the pharmaceutical industry. Ideally, the method to determine an OOT alarm should not be too complex. Various approaches have been used historically for the identification of OOT results, including the following:
● Three consecutive results are outside some limit.
● The difference between consecutive results is outside of half the difference between the prior result and the specification.
● The result is outside 5% of initial result.
● The result is outside 3% of previous result.
● The result is outside 5% of the mean of all previous results.
The advantages of these approaches are that they are easily implemented, easily understood, and usually do not require different limits for each time point. However, the major disadvantage is that these approaches do not have a statistical basis. You may kindly refer the article on Identification of Out-of-Trend stability results that I have uploaded for detailed information on this subject.
Thanks for the inputs. They are really useful. I have attached one more article on this subject.
Dear Mr. Jitendara,
Can you help me, how many minimum no of batches required for OOT, and is there a guideline?? How many batches we have to consider for studies , if Only 2-3 batches are manufactured in a year can we take these batches to study OOT?? Is there supporting guideline??
I couldnt find any guidelines but you may find one useful article on below link;
I am attaching FDA guidance on Out of Specifications where in some pages you may find useful info for OOT. Also attaching one article from Pharmtech. Also attaching one ppt file by WHO where in on slide 35 there is discussion on OOT.
Monitoring impurities and content in stability study is the general and mandatory and regulatory requirements through Out of trend(OOT).
But it is required to monitor for batch release also.
Organization shall fix the trend limits to investigate the impurities in API and FPP batch release.
For example i have product ABC.
One of the impurity spec limit is NMT 0.10%.
Regularly the ipmurity is coming about 0.05%.
Suddenly started getting 0.09% in my baches.
So what you people do for this out of your regular trend .
Dont you investigate the reason why its getting and reached almost your spec limit.
Tomoroow it may fail.
Dear sirs and my freinds please reply .
Out of Trend criteria must be considered based on the process capability. If your process is able to produce the results which are on either side of your specification limit, then the OOT should be calculated based on that. You can use statistical tools/softwares to calculate this.
THE PROCESS CAPABILITY APPILIES ONLY IF WE HAVE MANUFACTURED ENOUGH BATCHES AND HAVING ANALYTICAL DATA.
WHAT WILL BE THE APPROCH FOR E BATCH STABILITY DATA AND ITS OOT
It seems that , in the above eg: impurity level in your batches, regularly <0.05%, suddently increase in your impurity is to be investigated by using the following tools:
1) Whether any Vendor changed ?
2) Whether people changed or new arrival if any?? did the new persons trained for operating ? there may be lack of observation from the production person, during critical processing.
3) Analytical errors. Check QC people.
4) Dispenisng of materials /calibration status etc.
5) You can decide the trend, but when it goes beond the trend still if it complies with any pharmacopoiea specifications , you may release the material, however OOT investigation shall be carried out.
6) APQR/ process change control etc also you should check to ensure the trends.
7) What are degradation studies, check your process validations.
Discuss with your R&D
Thank you verymuch for providing veryuseful information and guidance.
Any way thanks for your guidance.
I did not get whether you understand my post or not.
You only siad if it deviates regular trend we need to do investigation as you said.
You are right.On what basis wil you do the above things????
That is through OOT.
I think you understand that we both are same line
We should investiagte all out of trend results in stability and as well as regular batches.
As per guidelines you have address and investigate every deviation in your manufacturing location. OOT is also a deviation. Its a trend deviation. For better clarification we devided deviations into INCIDENT,OOT,OOS ...etc
Good question. There is no guideline on OOT. However industry has made a practice of monitoring results for OOT in regular / batch release and in stability studies.
OOT is required to know that the manufacturing process is under full control in case of batch release. If there is any abnormal results i.e., results closer to the specifications then those shall be investigated as if it is not investigated and root causes are not identified and appropriate CAPA is not taken , then in future batches may be OOS.
Regarding stability, the results should always be compared with previous station results for any changes. If there is any degradation, impurities content may raise. OOT will be useful for making us alert on the retest periods and also through the statistical data, it can be interpreted when batch will fall out of specification.
Hope this clarifies all your doubts.